Functionalized azaaromatic compounds, such as pyridines, quinolines, and pyrimidines, may be used as substructures in biologically active compounds. For instance, functionalized azaaromatic compounds are useful in the pharmaceutical industry, such as in the treatment of central nervous system disorders.
Traditional methods and procedures for creating functionalized azaaromatic compounds employ metalation techniques. Azaaromatics may be metallated by the deprotonation of the azaaromatic compound using bases such as lithium amides. Although lithium amides, such as lithium diisopropylamide (LDA) and lithium tetramethylpiperidide, have been used to deprotonate azaaromatic compounds, lithium amides are often not a strong enough base to completely deprotonate the azaaromatic compound. Furthermore, yields of functionalized azaaromatics produced by deprotonation with lithium amides tend to be modest. The use of other alkyllithium reagents, such as n-butyllithium, has also been undesirable because alkyllithiums, such as n-BuLi or tert-BuLi, tend to nucleophilicly attack the imine functionality of the azaaromatic compounds. In some cases, alkyllithiums with a catalytic amount of a secondary amine present can effectively deprotonate azaaromatics. This “catalyzed metalation” technique often produces modest yields. The modest yields may result because there is competing addition of the alkyllithium to the carbon-nitrogen double bond. As an alternative, the use of stronger bases has been proposed and tested for functionalization reactions of azaaromatic compounds. For instance, strong bases and poor nucleophiles such as lithium 2,2,6,6-tetramethylpiperidine (LiTMP) and mesityllithium (MesLi) have been used to functionalize azaaromatic compounds. However, the use of LiTMP and MesLi in industrial practice to produce large quantities of functionalized azaaromatic compounds is limited because the reactants are not readily available, they often require very low temperatures and/or the formation processes cannot be easily adapted to large-scale commercial production processes.
Methods for facilitating the metalation of azaaromatic compounds, which are scalable and produce high yields, are therefore desirable. Furthermore, methods, processes, and compounds for facilitating the metalation of azaaromatic compounds and other chemical compounds are also desirable.